The longterm goal of these studies is to understand the physiological consequences of cerebral hypoxia, and how failure of normal homeostatic mechanisms contributes to cerebral disease. Much attention has been devoted to understanding how cerebrovascular reserve impacts cerebral disease, however this tells only half the story; to understand tolerance to the effects of hypoxia, we also need to know the potential to limit cerebral metabolic activity. The central premise of the current proposal is that during hypoxia or ischemia cerebral tissue viability can maintained if the cerebral blood flow (CBF) can be increased or oxygen metabolism (CMRO2) can be reduced, both of which lead to preservation of local tissue oxygenation (PtiO2). An important determinant of oxygen homeostasis is local CO2; we recently discovered that during hypoxia the influence of CO2 on CMRO2 is increased. Thus CO2 provides a mechanism to both increase CBF (and O2 delivery) and decrease CMRO2 (and O2 consumption). We hypothesize that regional hypoxia tolerance in the brain is determined by the local strength of these hemodynamic and metabolic responses to CO2 in hypoxia (increasing CBF and decreasing CMRO2), which both act to preserve tissue oxygenation. The goals of this project are to determine if CBF and CMRO2 (and hence PtiO2) exhibit this expected difference in CO2 sensitivity during hypoxia in regions with know differences in hypoxia sensitivity. Our methodology allows measurement of regional CBF and CMRO2 responses, based on a novel multi-compartment model Blood Oxygenation Level-dependent (BOLD) signals. In Aim 1 we will test the reproducibility and sources of variance of our new MRI measurements of regional CMRO2 reactivity to CO2 / hypoxia. In Aim 2 we test our hypothesis that regions that are resistant to ischemic insults are better able to maximize local CBF and CMRO2 sensitivity to local CO2. This proposal presents a novel approach to address basic mechanistic questions in cerebral ischemic pathophysiology. The endpoint of this study will be a validated method to characterize CMRO2 reactivity in hypoxia, and a test of our hypothesis regarding regional hypoxia vulnerability in the human brain. These studies will also establish the basis and limitations for translating these novel MRI tools to evaluate ischemic vulnerability in cerebral disease.